Publications
170 results found
Stephens J, Soni S, Boshier P, et al., 2023, Intra-alveolar Neutrophil-derived Microvesicles After One-lung Ventilation Are Associated With Post-operative Pulmonary Complications in Patients Undergoing Esophagectomy, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Baldi RF, Chen J, Thomas C, et al., 2023, Microvesicles Induce Alveolar Epithelial Cell Death Via TNF-Caspase Signalling During Ventilator-induced Lung Injury, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Baldi RF, Koh MW, Thomas C, et al., 2023, Ventilator-Induced Lung Injury Promotes Inflammation Within the Pleural Cavity in a Mouse Model, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Iki Y, Soni S, Yasuda T, et al., 2023, Neutrophil-derived Microvesicles Directly Enhance Endothelial Permeability Independent of Monocytes, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Cheng X, Iki Y, Stephens J, et al., 2023, Acid Sphingomyelinase Induces the Release of Alveolar Macrophage-derived Microvesicles During Acute Lung Injury, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Tan YY, O'Dea KP, Tsiridou DM, et al., 2023, Circulating myeloid cell-derived extracellular vesicles as mediators of indirect acute lung injury, American Journal of Respiratory Cell and Molecular Biology, Vol: 68, Pages: 140-149, ISSN: 1044-1549
Blood-borne myeloid cells, neutrophils and monocytes, play a central role in the development of indirect acute lung injury (ALI) during sepsis and noninfectious systemic inflammatory response syndrome. By contrast, the contribution of circulating myeloid cell–derived extracellular vesicles (EVs) to ALI is unknown, despite acute increases in their numbers during sepsis and systemic inflammatory response syndrome. Here, we investigated the direct role of circulating myeloid-EVs in ALI using a mouse isolated perfused lung system and a human cell coculture model of pulmonary vascular inflammation consisting of lung microvascular endothelial cells and peripheral blood mononuclear cells. Total and immunoaffinity-isolated myeloid (CD11b+) and platelet (CD41+) EVs were prepared from the plasma of intravenous LPS-injected endotoxemic donor mice and transferred directly into recipient lungs. Two-hour perfusion of lungs with unfractionated EVs from a single donor induced pulmonary edema formation and increased perfusate concentrations of RAGE (receptor for advanced glycation end products), consistent with lung injury. These responses were abolished in the lungs of monocyte-depleted mice. The isolated myeloid- but not platelet-EVs produced a similar injury response and the acute intravascular release of proinflammatory cytokines and endothelial injury markers. In the in vitro human coculture model, human myeloid- (CD11b+) but not platelet- (CD61+) EVs isolated from LPS-stimulated whole blood induced acute proinflammatory cytokine production and endothelial activation. These findings implicate circulating myeloid-EVs as acute mediators of pulmonary vascular inflammation and edema, suggesting an alternative therapeutic target for attenuation of indirect ALI.
Alton E, Lund-Palau H, Juarez-Molina C, et al., 2022, Correction of a chronic pulmonary disease through lentiviral vector-mediated protein expression, Molecular Therapy - Methods and Clinical Development, Vol: 25, Pages: 382-391, ISSN: 2329-0501
We have developed a novel lentiviral vector, pseudotyped with the F and HN proteins from Sendai virus (rSIV.F/HN), which produces long-lasting, high efficiency transduction of the respiratory epithelium. Here, we addressed whether this platform technology can secrete sufficient levels of a therapeutic protein into the lung to ameliorate a fatal pulmonary disease, as an exemplar of its translational capability. Pulmonary Alveolar Proteinosis (PAP) results from alveolar GM-CSF insufficiency, resulting in abnormal surfactant homeostasis and consequent ventilatory problems. Lungs of GM-CSF knockout mice were transduced with a single dose of rSIV.F/HN expressing murine (m)GM-CSF (1e5-92e7 TU/mouse); mGM-CSF expression was dose-related and persisted for at least 11 months. PAP disease biomarkers were rapidly and persistently corrected, but we noted a narrow toxicity/efficacy window. rSIV.F/HN may be a useful platform technology to deliver therapeutic proteins for lung diseases requiring long-lasting and stable expression of secreted proteins.
Baldi RF, Soni S, Patel BV, et al., 2022, Macrophage-Derived Microvesicles Induce Alveolar Epithelial Cell Death in an In Vitro Stretch Model, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Tsiridou DM, Sachouli E, Takata M, et al., 2022, Neutrophil-Derived Microvesicles Enhance Pulmonary Vascular Inflammation via a Toll-like Receptor 4 Signaling-Dependent Mechanism., FASEB J, Vol: 36 Suppl 1
BACKGROUND: Circulating neutrophil-derived microvesicles (NMVs) are markedly elevated during sepsis and therefore could have a role in the development of indirect acute lung injury (ALI). We recently found that NMV-enriched CD11b+ MVs, immunoaffinity isolated from lipopolysaccharide (LPS)-stimulated healthy volunteer blood, have potent pro-inflammatory activity in a human peripheral blood mononuclear cell (PBMC) and lung microvascular endothelial cell (HLMEC) coculture model of pulmonary vascular inflammation (1). By contrast, immunoaffinity isolated platelet-MVs (CD61+ ) produced negligible responses in these assays, suggesting specificity of the NMV-enriched CD11b+ MV, activity. Here, we investigated the signaling mechanisms responsible for NMV-mediated activation of monocytes and HLMECs in this model. METHODS: Heparinized blood from healthy donors was treated with LPS (100 ng/ml, 3 h) and NMVs (CD66b+ ) were isolated by positive immunoaffinity selection. NMVs were then incubated in PBMC-HLMEC cocultures for 4 h. NMV-induced responses were determined by flow cytometric quantification of cell surface activation markers (ICAM-1 for HLMECs, ICAM-1 and tissue factor for monocytes) and pro-inflammatory cytokine release by ELISA (TNFα, IL-8, IL-6, MCP-1). RESULTS: NMV-induced HLMEC activation required the presence of monocytes and was completely attenuated by anti-TNFα neutralizing antibody (ICAM-1: isotype control 302±103 vs anti-TNFα 66±29; p<0.01). Pharmacological inhibition of mitogen-activated protein kinases p38, MEK1-MEK2 and phosphoinositide-3 kinase ablated monocyte and HLMEC activation. Monocyte activation was prevented in the presence of the Toll-like receptor 4 (TLR4) inhibitor TAK-242 (e.g., TNFα release: vehicle 1108±257 vs TAK-242 16±12; p<0.001) and partially inhibited by an anti-TLR4 neutralizing antibody. However, the LPS inhibitor polymyxin-B had no effect on these responses, indicating that LP
Soni S, O'Dea K, Abe E, et al., 2022, Microvesicle-mediated communication within the alveolar space: mechanisms of uptake by epithelial cells and alveolar macrophages, Frontiers in Immunology, Vol: 13, ISSN: 1664-3224
Intra-alveolar microvesicles (MVs) are important mediators of inter-cellular communication within the alveolar space, and are key components in the pathophysiology of lung inflammation such as acute respiratory distress syndrome (ARDS). Despite the abundance of data detailing the pro-inflammatory effects of MVs, it remains unclear how MVs interact or signal with target cells in the alveolus. Using both in vivo and in vitro alveolar models, we analyzed the dynamics of MV uptake by resident alveolar cells: alveolar macrophages and epithelial cells. Under resting conditions, the overwhelming majority of MVs were taken up by alveolar macrophages. However, following lipopolysaccharide (LPS)-mediated inflammation, epithelial cells internalized significantly more MVs (p<0.01) whilst alveolar macrophage internalization was significantly reduced (p<0.01). We found that alveolar macrophages adopted a pro-inflammatory phenotype after internalizing MVs under resting conditions, but reduction of MV uptake following LPS pre-treatment was associated with loss of inflammatory phenotype. Instead, MVs induced significant epithelial cell inflammation following LPS pre-treatment, when MV internalization was most significant. Using pharmacological inhibitors, we interrogated the mechanisms of MV internalization to identify which endocytic pathways and cell surface receptors are involved. We demonstrated that epithelial cells are exclusively dependent on the clathrin and caveolin dependent endocytotic pathway, whereas alveolar macrophage uptake may involve a significant phagocytic component. Furthermore, alveolar macrophages predominantly engulf MVs via scavenger receptors whilst, epithelial cells internalize MVs via a phosphatidylserine/integrin receptor mediated pathway (specifically alpha V beta III), which can be inhibited with phosphatidylserine-binding protein (i.e. annexin V). In summary, we have undertaken a comprehensive evaluation of MV internalization within the alveolar
Tan YY, O'Dea KP, Patel BV, et al., 2022, Investigation of microvesicle uptake by mouse lung-marginated monocytes in vitro., Bio-protocol, Vol: 12, Pages: 1-1, ISSN: 2331-8325
Extracellular microvesicles (MVs) are released into the circulation in large numbers during acute systemic inflammation, yet little is known of their intravascular cell/tissue-specific interactions under these conditions. We recently described a dramatic increase in the uptake of intravenously injected MVs by monocytes marginated within the pulmonary vasculature, in a mouse model of low-dose lipopolysaccharide-induced systemic inflammation. To investigate the mechanisms of enhanced MV uptake by monocytes, we developed an in vitro model using in vivo derived monocytes. Although mouse blood is a convenient source, monocyte numbers are too low for in vitro experimentation. In contrast, differentiated bone marrow monocytes are abundant, but they are rapidly mobilized during systemic inflammation, and thus no longer available. Instead, we developed a protocol using marginated monocytes from the pulmonary vasculature as an anatomically relevant and abundant source. Mice are sacrificed by terminal anesthesia, the lungs inflated and perfused via the pulmonary artery. Perfusate cell populations are evaluated by flow cytometry, combined with in vitro generated fluorescently labelled MVs, and incubated in suspension for up to one hour. Washed cells are analyzed by flow cytometry to quantify MV uptake and confocal microscopy to localize MVs within cells (O'Dea et al., 2020). Using this perfusion-based method, substantial numbers of marginated pulmonary vascular monocytes are recovered, allowing multiple in vitro tests to be performed from a single mouse donor. As MV uptake profiles were comparable to those observed in vivo, this method is suitable for physiologically relevant high throughput mechanistic studies on mouse monocytes under in vitro conditions. Graphic abstract: Figure 1. Schematic of lung perfusate cell harvest and co-incubation with in vitro generated MVs. Created with BioRender.com.
Kulkarni HS, Lee JS, Bastarache JA, et al., 2022, Update on the Features and Measurements of Experimental Acute Lung Injury in Animals An Official American Thoracic Society Workshop Report, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 66, Pages: E1-E14, ISSN: 1044-1549
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- Citations: 43
Patel B, Mumby S, Johnson N, et al., 2022, Decision support system to evaluate ventilation in the acute respiratory distress syndrome (DeVENT study)-trial protocol, Trials, Vol: 23, Pages: 1-18, ISSN: 1745-6215
BackgroundThe acute respiratory distress syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator-induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patient’s physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS.MethodsWe will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS.DiscussionDespite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator-induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs’ pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. Hence, personalised management demands the application of mechanical ventilation according to the physiological state of the diseased lung at that time. Hence, there is significant rationale for the development of point-of-care clinical decision support systems which help personalise ventilatory strateg
Sachouli E, Tsiridou DM, Takata M, et al., 2022, Stimulation of Neutrophils in Whole Blood Enhances the Pro -inflammatory Activity of NeutrophilDerived Microvesicles, FASEB JOURNAL, Vol: 36, ISSN: 0892-6638
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Patel B, Mumby S, Johnson N, et al., 2021, Decision support system to evaluate VENTilation in the Acute Respiratory Distress Syndrome (DeVENT study) – Trial Protocol, Trials, ISSN: 1745-6215
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The Acute Respiratory Distress Syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patient’s physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>Despite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs’ pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. H
Koh MW, Baldi RF, Soni S, et al., 2021, Secreted extracellular cyclophilin a is a novel mediator of ventilator induced lung injury., American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 421-430, ISSN: 1073-449X
RATIONALE: Mechanical ventilation is a mainstay of intensive care but contributes to the mortality of patients through ventilator induced lung injury. Extracellular Cyclophilin A is an emerging inflammatory mediator and metalloproteinase inducer, and the gene responsible for its expression has recently been linked to COVID-19 infection. OBJECTIVES: Here we explore the involvement of extracellular Cyclophilin A in the pathophysiology of ventilator-induced lung injury. METHODS: Mice were ventilated with low or high tidal volume for up to 3 hours, with or without blockade of extracellular Cyclophilin A signalling, and lung injury and inflammation were evaluated. Human primary alveolar epithelial cells were exposed to in vitro stretch to explore the cellular source of extracellular Cyclophilin A, and Cyclophilin A levels were measured in bronchoalveolar lavage fluid from acute respiratory distress syndrome patients, to evaluate clinical relevance. MEASUREMENTS AND MAIN RESULTS: High tidal volume ventilation in mice provoked a rapid increase in soluble Cyclophilin A levels in the alveolar space, but not plasma. In vivo ventilation and in vitro stretch experiments indicated alveolar epithelium as the likely major source. In vivo blockade of extracellular Cyclophilin A signalling substantially attenuated physiological dysfunction, macrophage activation and matrix metalloproteinases. Finally, we found that patients with acute respiratory distress syndrome showed markedly elevated levels of extracellular Cyclophilin A within bronchoalveolar lavage. CONCLUSIONS: Cyclophilin A is upregulated within the lungs of injuriously ventilated mice (and critically ill patients), where it plays a significant role in lung injury. Extracellular Cyclophilin A represents an exciting novel target for pharmacological intervention.
Baldi RF, Soni S, Patel BV, et al., 2021, Microvesicle-Mediated Enhancement of TNF-Driven Apoptosis During VILI, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Soni S, Garner J, O'Dea K, et al., 2021, Intra-alveolar neutrophil-derived microvesicles are associated with disease severity in COPD, American Journal of Physiology: Lung Cellular and Molecular Physiology, Vol: 320, Pages: L73-L83, ISSN: 1040-0605
Despite advances in the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD), there is a distinct lack of biochemical markers to aid clinical management. Microvesicles (MVs) have been implicated in the pathophysiology of inflammatory diseases including COPD but their association to COPD disease severity remains unknown. We analysed different MV populations in plasma and bronchoalveolar lavage fluid (BALF) taken from sixty-two patients with mild to very severe COPD (51% male; mean age: 65.9 years). These patients underwent comprehensive clinical evaluation (symptom scores, lung function, exercise testing) and the capacity of MVs to be clinical markers of disease severity was assessed. We successfully identified various MV subtype populations within BALF (leukocyte, PMN (polymorphonuclear leukocyte i.e. neutrophil), monocyte, epithelial and platelet MVs) and plasma (leukocyte, PMN, monocyte and endothelial MVs), and compared each MV population to disease severity. BALF neutrophil MVs were the only population to significantly correlate with the clinical evaluation scores including FEV1, mMRC dyspnoea score, 6-minute walk test, hyperinflation and gas transfer. BALF neutrophil MVs, but not neutrophil cell numbers, also strongly correlated with BODE index. We have undertaken, for the first time, a comprehensive evaluation of MV profiles within BALF/plasma of COPD patients. We demonstrate that BALF levels of neutrophil-derived MVs are unique in correlating with a number of key functional and clinically-relevant disease severity indices. Our results show the potential of BALF neutrophil MVs for a COPD biomarker that tightly links a key pathophysiological mechanism of COPD (intra-alveolar neutrophil activation) with clinical severity/outcome.
Soni S, Romano R, O'Dea K, et al., 2020, Intra-alveolar neutrophil-derived microvesicles predict development of primary graft dysfunction after lung transplantation, 2020 ERS International Congress, Publisher: European Respiratory Society, Pages: 1-2, ISSN: 0903-1936
Background: Microvesicles (MV) play important roles in mediating intra-alveolar inflammation during acute lung injury. We investigated the MV profiles within bronchoalveolar lavage fluid (BALF) in patients undergoing lung transplantation and assessed relationship to the development of primary graft dysfunction (PGD).Methods: Lung transplant patients underwent bronchoscopy after completion of surgery and BALF samples (n=31) were analysed by flow cytometry for MVs derived from leucocytes (CD45+), neutrophils (CD66b+/CD11b+), monocytes (CD45+/CD14+), alveolar macrophages (CD206+/CD71+), platelets (CD31+/42b+) and epithelial (EpCAM+/T1α+) cells. MV numbers were correlated to clinical outcomes including hypoxia and development of PGD.Results: Various MV subpopulations were identified in BALF. Neutrophil-derived MVs were the largest population (10,548 (3,925-51,529)) compared to leucocyte MVs (9797 (4763-53444)), monocyte MVs (438 (196-25,627)), alveolar macrophage MVs (755 (343-6054) and platelets MVs (564 (286-953)) (MVs/µL, median (IQR)). Patients with PaO2/FiO2 (P/F) ratio ≤ 200mmHg at 72 hours had significantly higher levels of BALF neutrophil MVs than those with P/F ratio > 200mmHg (p=0.001). Patients who developed PGD also had significantly higher BALF neutrophil MVs than those who did not (p=0.03).Conclusions: We have undertaken a comprehensive evaluation of MVs within BALF of lung transplant recipients and demonstrated an association of BALF neutrophil MV numbers and PGD. Our data may suggest BALF neutrophil MVs as a potential, clinically relevant biomarker for PGD. Moreover, these MV may also have a pathogenic/inflammatory role in development of PGD
Tsiridou DM, O'Dea KP, Tan YY, et al., 2020, Late Breaking Abstract - Myeloid-derived microvesicles as acute mediators of sepsis-induced lung vascular inflammation, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Koh M, Takata M, Wilson M, 2020, Cyclophilin A as a Novel Mediator in Ventilator-Induced Lung Injury, Annual Meeting on Experimental Biology, Publisher: WILEY, ISSN: 0892-6638
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Tsiridou D, O'Dea K, Tan Y, et al., 2020, Neutrophil-Derived Microvesicle Uptake under Flow Conditions in an I<it>n Vitro</it> Model of Pulmonary Vascular Inflammation, Annual Meeting on Experimental Biology, Publisher: WILEY, ISSN: 0892-6638
Hua R, Edey LF, O'Dea KP, et al., 2020, CCR2 mediates the adverse effects of LPS in the pregnant mouse, Biology of Reproduction, Vol: 102, Pages: 445-455, ISSN: 0006-3363
In our earlier work, we found that intrauterine (i.u.) and intraperitoneal (i.p.) injection of LPS (10-μg serotype 0111:B4) induced preterm labor (PTL) with high pup mortality, marked systemic inflammatory response and hypotension. Here, we used both i.u. and i.p. LPS models in pregnant wild-type (wt) and CCR2 knockout (CCR2-/-) mice on E16 to investigate the role played by the CCL2/CCR2 system in the response to LPS. Basally, lower numbers of monocytes and macrophages and higher numbers of neutrophils were found in the myometrium, placenta, and blood of CCR2-/- vs. wt mice. After i.u. LPS, parturition occurred at 14 h in both groups of mice. At 7 h post-injection, 70% of wt pups were dead vs. 10% of CCR2-/- pups, but at delivery 100% of wt and 90% of CCR2-/- pups were dead. Myometrial and placental monocytes and macrophages were generally lower in CCR2-/- mice, but this was less consistent in the circulation, lung, and liver. At 7 h post-LPS, myometrial ERK activation was greater and JNK and p65 lower and the mRNA levels of chemokines were higher and of inflammatory cytokines lower in CCR2-/- vs. wt mice. Pup brain and placental inflammation were similar. Using the IP LPS model, we found that all measures of arterial pressure increased in CCR2-/- but declined in wt mice. These data suggest that the CCL2/CCR2 system plays a critical role in the cardiovascular response to LPS and contributes to pup death but does not influence the onset of inflammation-induced PTL.
Zöllner J, Howe LG, Edey LF, et al., 2020, LPS-induced hypotension in pregnancy: the effect of progesterone supplementation, Shock, Vol: 53, Pages: 199-207, ISSN: 1073-2322
Our previous work has shown that pregnancy exacerbates the hypotensive response to both infection and LPS. The high levels of progesterone (P4) associated with pregnancy have been suggested to be responsible for the pregnancy-induced changes in the cardiovascular response to infection. Here, we test the hypothesis that P4 supplementation exacerbates the hypotensive response of the maternal cardiovascular to LPS.Female CD1 mice had radiotelemetry probes implanted to measure haemodynamic function non-invasively and were time-mated. From day 14 of pregnancy, mice received either 10 mg of P4 or vehicle alone per day and on day 16, intraperitoneal LPS (10 μg of serotype 0111:B4) was injected. In two identically treated cohorts of mice, tissue and serum (for RNA, protein studies) were collected at 6 and 12 hours.Administration of LPS resulted in a fall in blood pressure in vehicle treated, but not P4 supplemented mice. This occurred with similar changes in the circulating levels of cytokines, vasoactive factors and in both circulating and tissue inflammatory cell numbers, but with reduced left ventricular expression of cytokines in P4-supplemented mice. However, left ventricular expression of markers of cardiac dysfunction and apoptosis were similar.This study demonstrates that P4 supplementation prevented LPS-induced hypotension in pregnant mice in association with reduced myocardial inflammatory cytokine gene expression. These observations suggest that rather than being detrimental, P4 supplementation has a protective effect on the maternal cardiovascular response to sepsis.
O'Dea K, Tan YY, Shah S, et al., 2020, Monocytes mediate homing of circulating microvesicles to the pulmonaryvasculature during low-grade systemic inflammation, Journal of Extracellular Vesicles, Vol: 9, Pages: 1-16, ISSN: 2001-3078
Microvesicles (MVs), a plasma membrane-derived subclass of extracellular vesicles, are produced and released into the circulation during systemic inflammation, yet little is known of cell/tissue-specific uptake of MVs under these conditions. We hypothesized that monocytes contribute to uptake of circulating MVs and that their increased margination to the pulmonary circulation and functional priming during systemic inflammation produces substantive changes to the systemic MV homing profile. Cellular uptake of i.v.-injected, fluorescently labelled MVs (J774.1 macrophage-derived) in vivo was quantified by flow cytometry in vascular cell populations of the lungs, liver and spleen of C57BL6 mice. Under normal conditions, both Ly6Chigh and Ly6Clow monocytes contributed to MV uptake but liver Kupffer cells were the dominant target cell population. Following induction of sub-clinical endotoxemia with low-dose i.v. LPS, MV uptake by lung-marginated Ly6Chigh monocytes increased markedly, both at the individual cell level (~2.5-fold) and through substantive expansion of their numbers (~8-fold), whereas uptake by splenic macrophages was unchanged and uptake by Kupffer cells actually decreased (~50%). Further analysis of MV uptake within the pulmonary vasculature using a combined model approach of in vivo macrophage depletion, ex vivo isolated perfused lungs and in vitro lung perfusate cell-based assays, indicated that Ly6Chigh monocytes possess a high MV uptake capacity (equivalent to Kupffer cells), that is enhanced directly by endotoxemia and ablated in the presence of phosphatidylserine (PS)-enriched liposomes and β3 integrin receptor blocking peptide. Accordingly, i.v.-injected PS-enriched liposomes underwent a redistribution of cellular uptake during endotoxemia similar to MVs, with enhanced uptake by Ly6Chigh monocytes and reduced uptake by Kupffer cells. These findings indicate that monocytes, particularly lung-marginated Ly6Chigh subset monocytes, become a dominant
Handslip R, Mumby S, Calfee CS, et al., 2020, Necrosome complex release and necroinflammation in hyper-inflammatory ARDS, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, Pages: 1-2, ISSN: 1073-449X
Tan YY, O'Dea KP, Takata M, 2020, Circulating Neutrophil-Derived Microvesicles During Endotoxaemia Induce Pulmonary Vascular Injury, Virtual International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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Oakley C, Koh M, Baldi R, et al., 2019, Ventilation following established ARDS: a preclinical model framework to improve predictive power, Thorax, Vol: 74, Pages: 1120-1129, ISSN: 1468-3296
Background Despite advances in understanding the pathophysiology of acute respiratory distress syndrome, effective pharmacological interventions have proven elusive. We believe this is a consequence of existing preclinical models being designed primarily to explore biological pathways, rather than predict treatment effects. Here, we describe a mouse model in which both therapeutic intervention and ventilation were superimposed onto existing injury and explored the impact of β-agonist treatment, which is effective in simple models but not clinically.Methods Mice had lung injury induced by intranasal lipopolysaccharide (LPS), which peaked at 48 hours post-LPS based on clinically relevant parameters including hypoxaemia and impaired mechanics. At this peak of injury, mice were treated intratracheally with either terbutaline or tumour necrosis factor (TNF) receptor 1-targeting domain antibody, and ventilated with moderate tidal volume (20 mL/kg) to induce secondary ventilator-induced lung injury (VILI).Results Ventilation of LPS-injured mice at 20 mL/kg exacerbated injury compared with low tidal volume (8 mL/kg). While terbutaline attenuated VILI within non-LPS-treated animals, it was ineffective to reduce VILI in pre-injured mice, mimicking its lack of clinical efficacy. In contrast, anti-TNF receptor 1 antibody attenuated secondary VILI within pre-injured lungs, indicating that the model was treatable.Conclusions We propose adoption of a practical framework like that described here to reduce the number of ultimately ineffective drugs reaching clinical trials. Novel targets should be evaluated alongside interventions which have been previously tested clinically, using models that recapitulate the (lack of) clinical efficacy. Within such a framework, outperforming a failed pharmacologic should be a prerequisite for drugs entering trials.
Soni S, Tirlapur N, O'Dea KP, et al., 2019, Microvesicles as new therapeutic targets for the treatment of the acute respiratory distress syndrome (ARDS), EXPERT OPINION ON THERAPEUTIC TARGETS, Vol: 23, Pages: 931-941, ISSN: 1472-8222
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Zhao H, Chen Q, Huang H, et al., 2019, Osteopontin mediates necroptosis in lung injury after transplantation of ischaemic renal allografts in rats, BRITISH JOURNAL OF ANAESTHESIA, Vol: 123, Pages: 519-530, ISSN: 0007-0912
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